HMGB1 represses the anti-cancer activity of sunitinib by governing TP53 autophagic degradation via its nucleus-to-cytoplasm transport.
HMGB1 represses the anti-cancer activity of sunitinib by governing TP53 autophagic degradation via its nucleus-to-cytoplasm transport.
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HMGB1 通过核到细胞质转运控制 TP53 自噬降解，从而抑制舒尼替尼的抗癌活性
DOI：
10.1080/15548627.2018.1501134
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发表时间：
2018
期刊：
影响因子：
13.3
通讯作者：
He Q
中科院分区：
文献类型：
--
作者：
Luo P;Xu Z;Li G;Yan H;Zhu Y;Zhu H;Ma S;Yang B;He Q
舒尼替尼是一种被批准用于多种癌症适应症的多激酶抑制剂，但其反应率很低。确定耐药机制可以导致合理的联合治疗方案，从而改善临床结果。在这里，我们报告了对舒尼替尼治疗的耐药性是由TP53/p53的自噬降解驱动的。ATG7或ATG5的缺失抑制了TP53的降解，SQSTM1/p62的敲低也是如此。从机制上讲，TP53从细胞核转运到细胞质是舒尼替尼诱导的TP53自噬降解所必需的，不需要TP53核输出信号（NESs）。此外，TP53的降解是通过其核结合靶点HMGB1的转运实现的，HMGB1将TP53从细胞核转移到细胞质中。HMGB1的抑制使癌细胞对舒尼替尼敏感。重要的是，舒尼替尼诱导了所有TP53蛋白的降解，除了在TP53与HMGB1（氨基酸313至352）相互作用区域发生突变的TP53蛋白。总之，我们的数据确定了HMGB1介导的TP53蛋白转换机制参与了舒尼替尼的耐药，并建议HMGB1作为改善舒尼替尼临床结果的潜在治疗靶点。
ABSTRACT Sunitinib, a multikinase inhibitor approved for a number of cancer indications has a low response rate. Identifying mechanisms of resistance could lead to rational combination regimens that could improve clinical outcomes. Here we report that resistance to sunitinib therapy was driven by autophagic degradation of TP53/p53. Deletion of ATG7 or ATG5 suppressed TP53 degradation, as did knockdown of SQSTM1/p62. Mechanistically, the transport of TP53 from the nucleus to the cytoplasm was essential for the sunitinib-induced autophagic degradation of TP53 and did not require TP53 nuclear export signals (NESs). Moreover, TP53 degradation was achieved by the transport of its nuclear binding target, HMGB1, which shifted TP53 from the nucleus to the cytoplasm. The inhibition of HMGB1 sensitized cancer cells to sunitinib. Importantly, sunitinib induced the degradation of all TP53 proteins, except for TP53 proteins with mutations in the interaction domain of TP53 with HMGB1 (amino acids 313 to 352). In conclusion, our data identify an alternative HMGB1-mediated TP53 protein turnover mechanism that participates in the resistance of sunitinib and suggest HMGB1 as a potential therapeutic target for improving clinical outcomes of sunitinib.
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影响因子：
4.3
作者：
Choudhury, Sujata;Kolukula, Vamsi K.;Avantaggiati, Maria Laura
通讯作者：
Avantaggiati, Maria Laura
DOI：
10.1073/pnas.1121146109
发表时间：
2012-05-08
影响因子：
11.1
作者：
Hayakawa, Kazuhide;Pham, Loc-Duyen D.;Lo, Eng H.
通讯作者：
Lo, Eng H.
影响因子：
4.8
作者：
Ding, Wen-Xing;Ni, Hong-Min;Yin, Xiao-Ming
通讯作者：
Yin, Xiao-Ming
影响因子：
64.8
作者：
Hessa, Tara;Sharma, Ajay;Mariappan, Malaiyalam;Eshleman, Heather D.;Gutierrez, Erik;Hegde, Ramanujan S.
通讯作者：
Hegde, Ramanujan S.
影响因子：
12.4
作者：
Liu, Ju;Zhang, C.;Feng, Z.
通讯作者：
Feng, Z.